Cardiac dilation is a common clinical phenomenon observed in several cardiac diseases, such as post-myocardial infarction and heart failure. In an early stage of cardiac dilation, the organ enlargement may be restricted to only a portion of the heart, such as the left ventricle. In an advanced stage, the complete heart may be enlarged. With each type of cardiac dilation, serious problems are associated which may include arrhythmias or leakage of the cardiac valves. Cardiac dilation is a frequent reason for subjecting a patient to heart transplantation.
Drugs (e.g. beta-adrenoceptor blockers, angiotensin converting enzyme inhibitors, aldosterone antagonists, digoxin, diuretics) are frequently employed for treating problems associated with cardiac dilation and heart failure. Yet, drugs can at best delay the natural progression of most cardiac diseases. Complete healing of myocardial dilation or heart failure has not been achieved so far.
Recently, passive ventricular restraint devices (e.g. CorCap Cardiac Support Device; Acorn Cardiovascular Inc., St. Paul, Minn., USA) have been applied to stop adverse LV remodelling and dilation in failing hearts, (Blom et al. (2005). Circulation; 112:1274-83). International application WO 98/58598, for example, describes an elastic plastic bag for avoiding an excessive dilation of the heart beyond a critical volume. U.S. Pat. No. 5,702,343 discloses a jacket for constraining cardiac expansion during diastole. US Patent application 2005/0085688 describes an elastic cardiac support device of a biocompatible material for constraining expansion of the heart without interfering with systolic contraction. Despite positive trials in Europe and North America, the use of cardiac support devices (CSD) has recently been stopped by the U.S. Food and Drug Administration due to safety concerns. It has been found that pericardial constriction may occur in patients with cardiac support devices making reoperations necessary which are technically challenging (Schroder et al. (2006), Eur J Cardiothorac Surg; 29:848-50).
The ex vivo-production of heart tissue by tissue engineering offers an alternative approach of preventing cardiac dilation and heart failure. Tissue engineering aims at generating functional three-dimensional tissues that can be tailored in size, shape and function according to the respective needs before implanting them into the body. Therapeutically applied artificial heart tissue should stabilize the failing heart to prevent further dilation and in addition add contractile elements to a dilated or failing heart. Several publications describe the in vitro generation of engineered myocardium in different geometrical sizes and shapes (Akins R E, et al. (1999), Tissue Eng, 5:103-18; Bursac N, et al. (1999), Am J Physiol, 277:H433-44; Carrier R L, et al. (1999), Biotechnol Bioeng; 64:580-9; Eschenhagen T, et al. (1997), Faseb J, 11:683-94; Leor J, et al. (2000). Circulation, 102:III 56-61; Li R K, et al. (1999). Circulation, 100:II 63-9; Shimizu T, et al. (2002). Circ Res, 90:E40; van Luyn M J, et al. (2002) Biomaterials, 23:4793-801; Zimmermann W H, et al. (2002). Circ Res., 90:223-30; Zimmermann W H, et al., (2000), Biotechnol Bioeng, 68:106-14). Engineered heart tissue can be reconstituted by mixing heart cells from rat (including cardiac myocytes, fibroblasts, smooth muscle cells, endothelial cells, macrophages and other cells of leukocytic origin, etc.) with collagen type I, MATRIGEL™ and culture medium, European application 05400038.5 describes the generation of engineered human heart tissue constructs derived from stem cells.
However, the generation of engineered tissue is technically challenging, since the size of the constructs appears to be limited by the maximum diffusion distances for nutrients and oxygen. Therefore, it was not possible so far to construct larger three-dimensional tissue constructs which are suitable to be used for stabilizing a large mammalian heart suffering from cardiac dilation.